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Inactivation of the cytoprotective major vault protein by caspase-1 and -9 in epithelial cells during apoptosis


Grossi, Serena; Fenini, Gabriele; Kockmann, Tobias; Hennig, Paulina; Di Filippo, Michela; Beer, Hans-Dietmar (2020). Inactivation of the cytoprotective major vault protein by caspase-1 and -9 in epithelial cells during apoptosis. Journal of Investigative Dermatology, 140(7):1335-1345.e10.

Abstract

Inflammasome activation induces caspase-1-dependent secretion of the proinflammatory cytokine IL-1β. In addition, caspase-1 activates the protein GSDMD in immune cells, causing pyroptosis, a lytic type of cell death. In contrast, UVB irradiation of human primary keratinocytes induces NLRP1 inflammasome activation, cytokine secretion, and caspase-1-dependent apoptosis, rather than pyroptosis. Here, we addressed the molecular mechanisms underlying the role of caspase-1 in UVB-induced cell death of human primary keratinocytes. We show that GSDMD is a poor substrate of caspase-1 in human primary keratinocytes and that its activation upon UVB irradiation supports secretion of IL-1β. We screened for novel substrates of caspase-1 by a mass spectrometry-based approach and identified the specific cleavage of the major vault protein (MVP) at D441 by caspase-1 and -9. MVP is the main component of vaults, highly conserved ribonucleoprotein particles, whose functions are poorly understood. Cleavage of MVP is a common event occurring in human primary keratinocytes and fibroblasts undergoing apoptosis induced by different stimuli. In contrast, MVP cleavage could not be detected in pyroptotic cells. Cleavage of MVP by caspase-1 and -9 inactivates this cytoprotective protein. These results demonstrate a proapoptotic activity of caspase-1 and a crosstalk with caspase-9 upon inactivation of the cytoprotective MVP in apoptotic epithelial cells.

Abstract

Inflammasome activation induces caspase-1-dependent secretion of the proinflammatory cytokine IL-1β. In addition, caspase-1 activates the protein GSDMD in immune cells, causing pyroptosis, a lytic type of cell death. In contrast, UVB irradiation of human primary keratinocytes induces NLRP1 inflammasome activation, cytokine secretion, and caspase-1-dependent apoptosis, rather than pyroptosis. Here, we addressed the molecular mechanisms underlying the role of caspase-1 in UVB-induced cell death of human primary keratinocytes. We show that GSDMD is a poor substrate of caspase-1 in human primary keratinocytes and that its activation upon UVB irradiation supports secretion of IL-1β. We screened for novel substrates of caspase-1 by a mass spectrometry-based approach and identified the specific cleavage of the major vault protein (MVP) at D441 by caspase-1 and -9. MVP is the main component of vaults, highly conserved ribonucleoprotein particles, whose functions are poorly understood. Cleavage of MVP is a common event occurring in human primary keratinocytes and fibroblasts undergoing apoptosis induced by different stimuli. In contrast, MVP cleavage could not be detected in pyroptotic cells. Cleavage of MVP by caspase-1 and -9 inactivates this cytoprotective protein. These results demonstrate a proapoptotic activity of caspase-1 and a crosstalk with caspase-9 upon inactivation of the cytoprotective MVP in apoptotic epithelial cells.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Health Sciences > Dermatology
Life Sciences > Cell Biology
Uncontrolled Keywords:Cell Biology, Biochemistry, Molecular Biology, Dermatology
Language:English
Date:1 July 2020
Deposited On:10 Sep 2020 16:10
Last Modified:23 Jun 2024 01:42
Publisher:Elsevier
ISSN:0022-202X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jid.2019.11.015
PubMed ID:31877317
Project Information:
  • : FunderFP7
  • : Grant ID239408
  • : Project TitleINNOV-MARKET - Incumbents' Innovation Strategy Choice Under Market Uncertainty